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The hepatitis B (HepB) vaccine represents the most effective strategy for preventing hepatitis B virus (HBV) infection. However, its immunogenicity is suboptimal in chronic kidney disease (CKD) patients due to immune system impairment and frequent requirements for immunosuppressive therapy (1-2). Additionally, patient adherence to the routine vaccination schedule remains inadequate (3). While shortened vaccination schedules can improve completion rates and potentially stimulate earlier and more rapid hepatitis B surface antibody (anti-HBs) production, high-dose HepB vaccination is specifically recommended for CKD patients and immunocompromised individuals by both the Advisory Committee on Immunization Practices (ACIP) and the Chinese Medical Association (4–5). However, the efficacy of combining short-course vaccination with high doses to rapidly and effectively induce immune responses and improve adherence in CKD patients remains unclear. In this study, 273 CKD patients were randomized into three groups receiving HepB vaccine following either the routine regimen, a short-course regimen, or a short-course high-dose regimen. Our results suggest that the short-course high-dose regimen can serve as an effective rapid immunization protocol for CKD patients, representing significant practical importance for HepB prevention and control in this vulnerable population.
This prospective study was conducted between May 2019 and February 2020 across four hospitals in Shanxi Province, China. Sample size calculations were based on a non-inferiority design, with an expected seroconversion rate of 80% following the routine regimen based on previous studies. Using PASS15 (NCSS, Kaysville, UT, US), we calculated a required sample size of 61 subjects per group, assuming a non-inferiority margin of -10%, one-sided α=0.025, and power=0.80. Accounting for an anticipated 20% loss to follow-up, we aimed to recruit 77 subjects per group. A total of 290 subjects were enrolled, with 273 randomized into three groups according to a randomization list generated using SAS statistical software (version 9.4, NC, SAS Institute Inc., USA). Inclusion criteria comprised: 1) written informed consent; 2) CKD diagnosis and age 18–70 years; and 3) negative status for hepatitis B surface antigen (HBsAg), anti-HBs, and hepatitis B core antibody (anti-HBc). Exclusion criteria included: 1) pregnancy or severe acute/chronic diseases (liver disease, blood disease, or cancer); 2) contraindications to HepB vaccination or vaccination history within one month of enrollment; and 3) HBV-DNA positivity or HBV-related glomerulonephritis. The Ethics Committee of Shanxi Medical University approved this study (Approval number: 2019007), and the trial was registered at ClinicalTrials.gov (CT.gov identifier: NCT03962881). Subjects received either 20 μg or 60 μg of HepB vaccine (Shenzhen Kangtai Biological Products Co., Ltd., China; Batch B201809043 and A201805008) following either a routine schedule (0-1-6 months, 20 μg) (IM0-1-6*20 group) or rapid schedules (0-1-2 months, 20 μg or 60 μg) (IM0-1-2*20 and IM0-1-2*60 groups). Blood samples were collected one month after the final vaccination dose (month 7 for IM0-1-6*20 group; month 3 for IM0-1-2*20 and IM0-1-2*60 groups) to measure geometric mean concentrations (GMCs) of anti-HBs. Anti-HBs levels were quantified using chemiluminescent microparticle immunoassay (ARCHITECT HBsAg/Anti-HBs Reagent Kit, Abbott Ireland Diagnostics Division, Finisklin Business Park, Sligo, Ireland). Anti-HBs concentrations <10 mIU/mL indicated non-response, while concentrations ≥10 mIU/mL and ≥100 mIU/mL defined seroconversion and high-response, respectively. CKD staging was determined by eGFR values: <15 (stage 5), 15–29 (stage 4), 30–59 (stage 3), 60–89 (stage 2), or ≥90 (stage 1).
Statistical analyses employed Pearson chi-square tests or Fisher’s exact tests for categorical data and one-way analysis of variance for continuous data. Factors influencing immunogenicity were evaluated using univariate and multivariate logistic regression models. All analyses were performed using SAS (version 9.4, NC, SAS Institute Inc., USA), with statistical significance set at P<0.05.
A total of 273 patients with CKD were randomized into three groups, with 224 completing the study: 71 patients in the IM0-1-6*20 group, 75 in the IM0-1-2*20 group, and 78 in the IM0-1-2*60 group (
Supplementary Figure S1 ). Patient characteristics were comparable across all three groups (Table 1) and between those who completed the study and those lost to follow-up (Supplementary Table S1 ).Variables N IM0-1-6*20 (n=71) IM0-1-2*20 (n=75) IM0-1-2*60 (n=78) χ2 P Gender Male 130 (58.0) 37 (52.1) 51 (68.0) 42 (53.9) 4.64 0.098 Female 94 (42.0) 34 (47.9) 24 (32.0) 36 (46.1) Age (years) <35 20 (8.9) 7 (9.9) 9 (12.0) 4 (5.1) 2.49 0.647 [35, 55) 122 (54.5) 37 (52.1) 40 (53.3) 45 (57.7) ≥55 82 (36.6) 27 (38.0) 26 (34.7) 29 (37.2) BMI (kg/m2) <18.5 2 (0.9) 0 (0.0) 2 (2.7) 0 (0.0) 5.73 0.220 [18.5, 24) 77 (34.4) 26 (36.6) 21 (28.0) 30 (38.5) ≥24 145 (64.7) 45 (63.4) 52 (69.3) 48 (61.5) Area type Urban 58 (25.9) 21 (29.6) 15 (20.0) 22 (28.2) 2.08 0.354 Rural 166 (74.1) 50 (70.4) 60 (80.0) 56 (71.8) Level of education Primary school or lower 36 (16.1) 12 (16.9) 13 (17.3) 11 (14.1) 2.07 0.723 Junior high school 112 (50.0) 34 (47.9) 34 (45.3) 44 (56.4) Senior high school or higher 76 (33.9) 25 (35.2) 28 (37.4) 23 (29.5) Type of clinical diagnosis Nephrotic syndrome 129 (57.6) 40 (56.3) 49 (65.3) 40 (51.2) 4.54 0.337 Nephritic syndrome 12 (5.4) 5 (7.0) 4 (5.3) 3 (3.9) Others (renal tubular disorders,
polycystic kidney, and unclear)83 (37.0) 26 (36.7) 22 (29.4) 35 (44.9) Duration of chronic kidney disease (years) ≤3 176 (78.6) 55 (77.5) 60 (80.0) 61 (78.2) 0.15 0.928 >3 48 (21.4) 16 (22.5) 15 (20.0) 17 (21.8) CKD stage Stage 1 84 (37.5) 34 (47.9) 26 (34.7) 24 (30.7) 9.63 0.292 Stage 2 62 (27.7) 18 (25.3) 21 (28.0) 23 (29.5) Stage 3 27 (12.1) 8 (11.3) 7 (9.3) 12 (15.4) Stage 4 44 (19.6) 8 (11.3) 18 (24.0) 18 (23.1) Stage 5 7 (3.1) 3 (4.2) 3 (4.0) 1 (1.3) History of HepB vaccine Yes 20 (8.9) 4 (5.6) 6 (8.0) 10 (12.8) 4.73 0.316 No 152 (67.9) 46 (64.8) 55 (73.3) 51 (63.4) Unknown 52 (23.2) 21 (29.6) 14 (18.7) 17 (21.8) Taking hormones/immunosuppressants Yes 94 (42.0) 30 (42.2) 29 (38.7) 35 (44.9) 0.61 0.738 No 130 (58.0) 41 (57.8) 46 (61.3) 43 (55.1) Note: Chronic kidney disease staging was defined by estimated eGFR as follows: Stage 5: <15 mL/min; Stage 4: 15–29 mL/min; Stage 3: 30–59 mL/min; Stage 2: 60–89 mL/min; Stage 1: ≥90 mL/min.
Abbreviation: BMI=body mass index; CKD=chronic kidney disease; HepB=hepatitis B; eGFR=estimated glomerular filtration rate.Table 1. Characteristics of chronic kidney disease patients who completed the full vaccination course in China from May 2019 to February 2020.
Following complete vaccination, the GMCs of anti-HBs were 1,675.2 (866.1, 2,484.4), 280.2 (170.9, 389.5), and 824.1 (86.38, 1,561.8) mIU/mL in the IM0-1-6*20, IM0-1-2*20, and IM0-1-2*60 groups, respectively (F=4.79, P=0.009). Seroconversion rates were 81.7%, 77.3%, and 88.5% (χ2=3.35, P=0.187), while high-response rates were 69.0%, 44.0%, and 64.1% for the respective groups (χ2=10.75, P=0.005). Both GMCs and high-response rates were significantly higher in the IM0-1-6*20 and IM0-1-2*60 groups compared to the IM0-1-2*20 group (P<0.05), with no significant differences between IM0-1-6*20 and IM0-1-2*60 groups (P>0.05) (Table 2). The incidence of total adverse reactions post-vaccination was comparable across groups: 8.8% (8/91), 7.7% (7/91), and 9.9% (9/91) in the IM0-1-6*20, IM0-1-2*20, and IM0-1-2*60 groups, respectively (χ2=0.274, P=0.872). Pain and erythema were the most commonly reported adverse reactions, all of which were minor. Additionally, vaccination completion rates were numerically higher in the IM0-1-2*20 (82.4%) and IM0-1-2*60 (85.7%) groups compared to the IM0-1-6*20 group (78.0%) (χ2=1.84, P=0.398).
Response IM0-1-6*20 (n=71) IM0-1-2*20 (n=75) IM0-1-2*60 (n=78) GMC, mIU/mL (95% CI) 1,675.2 (866.1, 2,484.4)* 280.2 (170.9, 389.5)† 824.1 (86.38, 1,561.8)* Seroconversion rate, % (95% CI) 81.7 (71.2, 89.0) 77.3 (66.7, 85.3) 88.5 (79.5, 93.8) High-response rate, % (95% CI) 69.0 (57.5, 78.6)* 44.0 (33.3, 55.3)† 64.1 (53.0, 73.9)* Note: group with * or † indicates no significant differences between two groups (P>0.05); group with † and * indicates significant differences between two groups (P<0.05).
Abbreviation: CKD=chronic kidney disease; GMC=geometric mean concentration; CI=confidence interval.Table 2. Immune responses to different hepatitis B vaccination regimens in chronic kidney disease patients in China from May 2019 to February 2020.
After adjusting for gender, age, residence, type of chronic kidney disease, and disease duration, patients who did not receive hormones/immunosuppressants demonstrated a significantly lower non/low-response rate [adjusted odds ratio (aOR): 2.59; 95% confidence interval (CI): 1.39-4.83, P=0.003] (
Supplementary Tables S2–S3 ). Stratification analysis by immunosuppression or hormone therapy status revealed that among patients without such therapy, the high-response rates (75.6%, 79.1%) and GMCs of anti-HBs (1,937.0, 901.4 mIU/mL) in the IM0-1-6*20 and IM0-1-2*60 groups were significantly higher than those in the IM0-1-2*20 group (52.2%, 337.7 mIU/mL) (P<0.05). Seroconversion rates were marginally higher in the IM0-1-6*20 and IM0-1-2*60 groups (87.8%, 93.0%) compared to the IM0-1-2*20 group (82.6%) (P>0.05). Among patients receiving immunosuppression or hormone therapy, both IM0-1-6*20 and IM0-1-2*60 groups showed numerically higher seroconversion rates, high-response rates, and GMCs of anti-HBs compared to the IM0-1-2*20 group (P>0.05) (Table 3).Response Taking hormones/immunosuppressants Yes No GMC, mIU/mL (95% CI) IM0-1-6*20 1,317.5 (441.2, 2,193.7) 1,937.0 (663.0, 3,211.0)* IM0-1-2*20 189.0 (1.91, 379.8) 337.7 (203.0, 472.4)† IM0-1-2*60 729.0 (154.9, 1,613.0) 901.4 (260.4, 2,603.3)† P 0.119 0.016 Seroconversion rate, % (95% CI) IM0-1-6*20 73.3 (55.6, 85.8) 87.8 (74.4, 94.7) IM0-1-2*20 68.9 (50.8, 82.7) 82.6 (69.3, 90.9) IM0-1-2*60 82.9 (67.3, 91.9) 93.0 (81.4, 97.6) P 0.413 0.327 High-response, % (95% CI) IM0-1-6*20 60.0 (42.3, 75.4) 75.6 (60.7, 86.2)* IM0-1-2*20 31.0 (17.3, 49.2) 52.2 (38.1, 65.9)† IM0-1-2*60 45.7 (30.5, 61.8) 79.1 (64.8, 88.6)* P 0.083 0.012 Note: group with * or † indicates no significant differences between two groups (P>0.05); group with † and * indicates significant differences between two groups (P<0.05).
Abbreviation: CKD=chronic kidney disease; GMC=geometric mean concentration; CI=confidence interval.Table 3. Vaccination responses in chronic kidney disease patients stratified by immunosuppressive or hormone therapy status in China from May 2019 to February 2020.
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This study represents the first investigation of short-course, high-dose HepB vaccination immunogenicity in CKD patients. We compared three vaccination regimens: the routine regimen (0-1-6 months, 20 μg), a short-course regimen (0-1-2 months, 20 μg), and a short-course, high-dose regimen (0-1-2 months, 60 μg). These findings demonstrate that the short-course, high-dose regimen achieved comparable immunogenicity to the routine regimen and can serve as an effective rapid immunization protocol for CKD patients. These results have important implications for optimizing HepB vaccine immunization strategies among CKD patients and advancing toward the goal of HepB elimination by 2030.
Previous research has demonstrated that short-course immunization (0-1-2 months) with 10 μg recombinant HepB vaccine induces comparable immune responses to routine immunization in healthy populations, achieving seroconversion rates of 84.6%–89.4% (6-7). In high-risk populations such as drug users, short-course regimens (0-1-2 months, 20 μg) produced seroconversion rates (65%) similar to routine regimens (62%) (8). In this CKD patient cohort, the short-course regimen yielded a 77.3% seroconversion rate, marginally lower than the routine regimen’s 81.7%. The variation in seroconversion rates across studies can be attributed to population differences and vaccination dosages. These findings suggest that while short-course immunization can effectively provide rapid protection, it demonstrates slightly reduced GMC and high-response rates compared to routine regimens in CKD patients.
Higher vaccine doses consistently produce elevated GMCs of anti-HBs and enhanced immune responses. Previous research in HIV patients demonstrated that a higher dose (40 μg) short-course regimen significantly increased GMCs (398.0 IU/L vs. 158.5 IU/L) and high-response rates (80.6% vs. 50.0%) compared to standard-dose (20 μg) short-course vaccination (9). This study is the first to examine whether higher doses in short-course regimens can rapidly and effectively induce enhanced immune responses in CKD patients. We found that the short-course, high-dose regimen achieved immunogenicity comparable to routine vaccination, producing GMCs of 824.1 mIU/mL and a high-response rate of 64.1%. This regimen demonstrated significantly superior immunogenicity compared to the standard-dose short-course regimen. Furthermore, extensive research and clinical experience have established the safety profile of HepB vaccines. This study corroborated these findings, with no serious adverse events reported following short-course, high-dose vaccination. Therefore, to rapidly and effectively generate protective anti-HBs, we recommend short-course, high-dose HepB vaccination for CKD patients.
Chronic kidney disease patients frequently require immunosuppressive or hormone therapy, which can significantly attenuate protective immunity (4). Feng et al. (10) identified immunosuppression or hormone therapy as an independent risk factor affecting HepB vaccine immunogenicity. Consistent with these findings, this study demonstrated that CKD patients receiving hormones/immunosuppressants exhibited higher rates of non/low-response status and diminished overall immunogenicity. However, this pattern was not observed in patients who did not receive such therapy. Further stratification analysis revealed that among patients not taking hormones/immunosuppressants, both the short-course, high-dose and routine regimens induced comparable seroconversion and high-response rates, which exceeded those of the short-course regimen. The short-course, high-dose regimen generated GMCs of 901.4 mIU/mL. Although this was lower than the routine regime group, the short-course vaccination offered key advantages of earlier protection and improved vaccination completion rates. Therefore, to achieve optimal seroconversion, CKD patients should receive short-course, high-dose HepB vaccination prior to initiating immunosuppressive therapy.
This study had several limitations. First, while immune response was assessed one month post-vaccination, the duration of protective effect could not be fully evaluated due to the limited follow-up period. Extended follow-up studies are needed to determine the longevity of anti-HBs maintenance. Second, patient attrition during follow-up resulted in reduced sample sizes for analysis as the study progressed.
In conclusion, short-course, high-dose HepB vaccination demonstrated immunogenicity comparable to routine regimens in CKD patients. This short-course, high-dose protocol can be recommended as a rapid immunization strategy for CKD patients, particularly when administered before immunosuppressive therapy.
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